Compositions for delivery of reboxetine

ABSTRACT

Described herein are methods for the administration of reboxetine, or a pharmaceutically acceptable salt thereof, to a human being in need thereof, resulting in a first maximum plasma concentration and a second maximum plasma concentration, wherein the two maxima are separated by a time period of about 2 hours to about 6 hours.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International Pat. App.No. PCT/US2019/037500, filed Jun. 17, 2019; which claims the benefit toU.S. Provisional Pat. App. Nos. 62/686,075, filed Jun. 17, 2018;62/688,333, filed Jun. 21, 2018; and 62/837,002, filed Apr. 22, 2019;all of which are incorporated by reference in their entirety.

FIELD

This disclosure relates to methods of administering or deliveringreboxetine to human beings.

BACKGROUND

Reboxetine is a norepinephrine reuptake inhibitor that is marketed as anantidepressant, and sold in as an oral drug sold under the brand nameEdronax®.

SUMMARY

This disclosure recognizes a need for dosage forms comprising reboxetinewith different pharmacokinetic properties. The present disclosure alsorelates to the use of such dosage forms for the treatment of one or moreconditions in a subject suitable for treatment by reboxetine orpharmaceutically acceptable salts thereof.

In human patients, reboxetine is rapidly absorbed, and peak levels areobserved within about 2 hours of dosing. Due to its rapid absorption andmetabolism, it is desirable to provide different formulations ofreboxetine, or pharmaceutically acceptable salts of reboxetine, that mayachieve multiple drug concentration maxima within a daily dosageregimen.

The present disclosure describes methods for providing reboxetine to theblood of a human being comprising administering reboxetine to a humanbeing in need of treatment of reboxetine wherein the reboxetine isadministered in a manner that results in 1) a first local maximum inreboxetine plasma concentration and 2) a second local maximum inreboxetine plasma concentration. The first local maximum will occur lessthan about 12 or less than about 10 hours prior to the second localmaximum, such as about 2 hours to about 6 hours prior to the secondlocal maximum. Normally, but not necessarily, the first local maximum inreboxetine plasma concentration and the second local maximum inreboxetine plasma concentration are the only maxima in reboxetine plasmaconcentration that occur within a single day.

Some embodiments include a dosage form comprising reboxetine, ormanufacture of a dosage form comprising reboxetine, that, whenadministered orally, provides the first local maximum in reboxetineplasma concentration and the second local maximum in reboxetine plasmaconcentration, as described herein, to the human being to whom thedosage form has been administered.

These methods and dosage forms may be used to treat psychiatric orneurological disorders.

Some embodiments include a kit or product comprising one or more dosageforms comprising reboxetine described herein with a label that describesor instructs using the dosage forms as described herein to treatpsychiatric or neurological disorders.

DETAILED DESCRIPTION

Unless otherwise indicated, any reference to a compound herein, such asreboxetine, by structure, name, or any other means, includespharmaceutically acceptable salts; free acids or bases; alternate solidforms, such as polymorphs, solvates, hydrates, etc.; tautomers;enantiomers; deuterium modified compounds, such as deuterium modifiedreboxetine; or any chemical species that may rapidly convert to acompound described herein under conditions in which the compounds areused as described herein.

Reboxetine may be represented by the structure below, which is themesylate salt.

In some embodiments, reboxetine is in a salt form, a free base form, ormay contain an excess (e.g. at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 97%, or at least 99%) of(+)-reboxetine or an excess (e.g. at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 97%, or at least 99%)(−)-reboxetine.

As mentioned above, for the methods described herein, the reboxetine isadministered in a manner that results in 1) a first local maximum inreboxetine plasma concentration and 2) a second local maximum inreboxetine plasma concentration. For convenience, any method thatresults in a first local maximum in reboxetine and a second localmaximum in reboxetine in a period substantially less than 12 hours, willbe referred to as a “subject method.”

In some embodiments, the first dosage form administered in a day, theonly dosage form administered during the day, or the first of two dosageor more dosage forms administered during the day, is administeredshortly after waking, such as within about 3 hours, within about 2hours, within about 1.5 hours, within about 1 hour, within about 30minutes, or within about 15 minutes of waking from an overnight sleep.

There are many potential ways that reboxetine could be administered in amanner that results in a first local maximum in reboxetine plasmaconcentration and a second local maximum in reboxetine plasmaconcentration. One method involves administering a single dosage formcomprising a first release component and a second release component.Both the first release component and the second release componentcomprise reboxetine.

The first release component may release reboxetine, may begin releasingreboxetine, or may have a first local maximum in the plasmaconcentration of reboxetine, about 0-30 minutes, about 30-60 minutes,about 60-90 minutes, or about 90-120 minutes after the dosage form isorally administered, or any time period in a range bounded by any ofthese values. The second release component may release reboxetine afterthe first release component releases reboxetine, or may cause anincrease of reboxetine plasma concentration or a second local maximum inthe plasma concentration of reboxetine, that is about 1-10 hours, about2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5hours, about 5-6 hours, about 6-7 hours, about 1-3 hours, about 2-4hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8hours, or about 7-10 hours after reboxetine is first released from thefirst release component, or after the first local maximum in the plasmaconcentration of reboxetine, or at any time in a range bounded by any ofthese values.

The subject method may be carried out repeatedly for an extended periodof time, e.g. at least 2 consecutive days, at least 7 consecutive days,at least 14 consecutive days, at least 28 consecutive days, at least 56consecutive days, at least 60 consecutive days, or longer.

The first release component and the second release component may beincorporated into one single dosage form (such as a pill, tablet,capsule, caplet, or cachou). In one embodiment, the first releasecomponent would be located in one of the outer layers of the dosage formand the second release component would be located in one of the innerlayers of the same dosage form.

In another embodiment, the first release component is located in a firstlayer of the dosage form, and the second release component is located ina second layer of the same dosage form. The two layers are distinct andmay or may not be in contact with one another. In some embodiments, thetwo layers are stacked on top of one another and physically bound in abi-layer structure (e.g. where the largest surfaces of the two layerscontact one another, or the layers are thin compared to the otherdimensions of the layers). In some embodiments, the two layers arepositioned next to one another and physically bound in a bi-layerstructure (e.g. where the layers are thicker than other dimensions ofthe layers).

In another embodiment, the first release component and the secondrelease component may be constructed separately in their own specificgranules, particles, or the like, wherein the first release componentparticles are formulated to release reboxetine before the second releasecomponent particles release reboxetine and wherein particles of bothrelease profiles are combined together into a single dosage form, suchas a capsule, pill, tablet, caplet, cachou or the like, and the tworelease components may or may not be physically bound to one another.

Another potential way to administer reboxetine in a manner that resultsin a first local maximum in reboxetine plasma concentration and a secondlocal maximum in reboxetine plasma concentration is to administer afirst dosage form containing reboxetine and, at a later time, a seconddosage form containing reboxetine. The doses are administered at timesthat result in a first local maximum in reboxetine plasma concentrationand a second local maximum in reboxetine plasma concentration. Forexample, the second dosage form may be administered less than half a dayafter the first dosage form, e.g. about 1-8 hours, about 8-12 hours,about 2-6 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours,about 5-6 hours, about 6-7 hours, about 1-3 hours, about 2-4 hours,about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, orabout 7-10 hours, after the first dosage form, or any time period in arange bounded by any of these values.

In some embodiments, the first local maximum occurs about 1-30 minutes,about 30-60 minutes, about 1-2 hours, about 2-3 hours, or about 3-4hours after the single dosage form or the first dosage form isadministered, or at any time in a range bounded by any of these values.Generally, the second local maximum occurs less than half a day afterthe first local maximum, such as about 1-10 hours, about 2-6 hours,about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours,about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours,about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, orabout 7-10 hours, after the first local maximum, or any time period in arange bounded by any of these values.

In some embodiments, two distinct maximum plasma concentrations areachieved by administering a first dosage form containing reboxetine and,at about the same time, a second dosage form containing reboxetine. Inthis example, the first dosage form and the second dosage form would becoated or formulated differently, such that the second local maximum(arising from the second dosage form) occurs less than half a day afterthe first local maximum (arising from the first dosage form), such asabout 1-10 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours,about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours,about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours,about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours,after the first local maximum.

For dosage forms containing a first release component and a secondrelease component, the first release component is associated with thefirst local maximum in reboxetine plasma concentration in that the firstrelease component releases the reboxetine that contributes to the firstlocal maximum in reboxetine plasma concentration. For example, the firstrelease component could release reboxetine faster or sooner than thesecond release component, so that most of the reboxetine contributing tothe first local maximum was released from the first release component.

For dosage forms containing a first release component and a secondrelease component, the second release component is associated with thesecond local maximum in reboxetine plasma concentration in that thesecond release component releases the reboxetine that contributes to thesecond local maximum in reboxetine plasma concentration. For example,the second release component could delay release of its reboxetine sothat at a time when the reboxetine plasma concentration is decreasingafter the first local maximum, the second release component releases asufficient amount of reboxetine to again increase the plasmaconcentration so that the second local maximum in reboxetine plasmaconcentration is achieved.

For dosage forms containing a first release component and a secondrelease component, any suitable amount of reboxetine may be present inthe first release component, such as about 1-10 mg, about 0.1-2 mg,about 0.5-1.5 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5mg, about 5-6 mg, about 6-7 mg, about 1-3 mg, about 2-4 mg, about 3-5mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 3-7 mg, about 4 mg,or any amount in a range bounded by any of these values.

For dosage forms containing a first release component and a secondrelease component, any suitable amount of reboxetine may be present inthe second release component, such as about 0.1-2 mg, about 0.5-1.5 mg,about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about2.5-3.5 mg, about 3-4 mg, about 2-4 mg, about 3-5 mg, about 3.5-4.5 mg,about 4-5 mg, about 4.5-5.5 mg, about 4-6 mg, about 6-7 mg, about 5-7mg, about 7-10 mg, about 3-7 mg, about 4 mg, or any amount in a rangebounded by any of these values.

In some embodiments, the first release component provides immediaterelease of reboxetine. In some embodiments, the first release componentprovides delayed release of reboxetine. In some embodiments, the firstrelease component provides sustained release of reboxetine.

In some embodiments, the second release component provides immediaterelease of reboxetine. In some embodiments, the second release componentprovides delayed release of reboxetine. In some embodiments, the secondrelease component provides sustained release of reboxetine.

In some embodiments, the first release component provides immediaterelease of reboxetine, and the second release component provides delayedrelease of reboxetine. In some embodiments, the first release componentprovides immediate release of reboxetine, and the second releasecomponent provides sustained release of reboxetine.

With respect to methods wherein the reboxetine is administered in afirst dosage form containing reboxetine and a second dosage formcontaining reboxetine, any suitable amount of reboxetine may be presentin the first dosage form, such as about 1-10 mg, about 0.1-2 mg, about0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg,about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 2-4 mg, about 3-5 mg,about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, or any amount ina range bounded by any of these values.

With respect to methods wherein the reboxetine is administered in afirst dosage form containing reboxetine and a second dosage formcontaining reboxetine, any suitable amount of reboxetine may be presentin the second dosage form, such as about 0.1-2 mg, about 0.5-1.5 mg,about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5mg, about 5-6 mg, about 6-7 mg, about 2-4 mg, about 3-5 mg, about 4-6mg, about 5-7 mg, about 7-10 mg, about 4 mg, or any amount in a rangebounded by any of these values.

In some embodiments, the first dosage form provides immediate release ofreboxetine. In some embodiments, the first dosage form provides delayedrelease of reboxetine. In some embodiments, the first dosage formprovides sustained release of reboxetine.

In some embodiments, the second dosage form provides immediate releaseof reboxetine. In some embodiments, the second dosage form providesdelayed release of reboxetine. In some embodiments, the second dosageform provides sustained release of reboxetine.

With respect to single dosage forms containing both a first releasecomponent and a second release component, in some embodiments, thedosage is administered within two hours of waking from an overnightsleep.

For some embodiments wherein more than one dosage form is given, thefirst dosage form may be administered within two hours of waking from anovernight sleep.

Controlled Release

There are many factors that can affect the overall time required for adrug substance such as reboxetine to be fully absorbed and/or reach amaximum plasma concentration in a human being. Among these factors is ahuman patient's age, weight, gender, level of stress, stomach contents,stomach pH level, and the presence of other medications. The time tomaximum plasma concentration may also be affected by the time of daytaken and the level of physical activity of the human patient. Anotherfactor that can affect the time to maximum plasma concentration is thepresence or absence of a controlled release coating.

Controlled release includes: immediate release of drug substance such asreboxetine at a certain time or in a certain area of the body; delayedrelease of a drug substance; sustained release of drug substance at acertain time or place in the body; or an extended release of a drugsubstance.

Reboxetine is normally rapidly absorbed in human patients, reaching amaximum plasma concentration in about 2-4 hours. To achieve a delay inthe time required to reach a maximum plasma concentration, a controlledrelease coating or mixture may be employed.

Delayed release is a general drug delivery term that describes the formof an oral medication that does not immediately discharge its activedrug component in the mouth or in the stomach of a patient. While theremay be many ways to achieve delayed release, delayed release may beachieved by completely or partially surrounding the reboxetine, e.g. inthe second release component with a coating or layer (e.g. an innercontrolled release coating) that does not immediately dissolve whenswallowed. For example, the material of the coating or layer may slowlydissolve in the stomach, and/or slowly disintegrate by chemicalreaction, such as by hydrolysis, in the stomach until the layer can nolonger prevent the reboxetine from coming into contact with the gastricfluid.

In some embodiments, the delayed release coating ensures deliverythrough the stomach and into the intestines. Once in the duodenum, thecoating may begin to break down and begin to release reboxetine. In somecases, the reboxetine may be completely released in the duodenum. Insome embodiments, the reboxetine may be partially released in theduodenum, and partially released in the jejunum. In some cases, thereboxetine may be completely released in the jejunum. In some cases, thereboxetine may be partially released in the jejunum and partiallyreleased in the ilium. In some cases, the reboxetine may be completelyreleased in the ilium. In some cases, the reboxetine may be partiallyreleased in the duodenum, the jejunum, and the ilium. In someembodiments, the reboxetine may be partially released in the ilium, andpartially released in the colon. In some cases, the reboxetine may becompletely released in the colon.

The time of the delayed release, e.g. between release of the firstreboxetine component and the second reboxetine component, can beadjusted by using a material that dissolves or disintegrates more orless slowly in the digestive system, adjusting the thickness of thelayer or coating (e.g. a thicker layer would provide a longer time),and/or by using materials whose properties are sensitive to pH. Forexample, materials that are less stable to, or more soluble in, acidicpHs, may dissolve or disintegrate more quickly in the stomach becausethe stomach pH is lower than the pH in the intestines. Conversely,materials that are stable at low pH, but less stable at higher pH maydissolve or disintegrate later because of the time it takes the dosageform to travel through the gastrointestinal tract.

A controlled release formulation containing reboxetine can be coatedwith one or more functional or non-functional coatings. Examples offunctional coatings include controlled release polymeric coatings (i.e.controlled release coats), moisture barrier coatings, enteric polymericcoatings, and the like.

A controlled release polymer may be used for both sustained release orfor delayed release, depending upon the structure of the dosage form.For example, interspersing the reboxetine throughout a controlledrelease polymer can provide sustained release, since the drug will bereleased for as long as the polymer is present in the GI tract. Delayedrelease may be achieved by creating a barrier, such as a coating, whichis intended to last for a shorter time (e.g. less than 12 hours, lessthan 10 hours, less than 6 hours, less than 3 hours, etc.), so that whenthe barrier is penetrated, the reboxetine is freely released. Thethickness of the barrier can be used to control the delay time.

Any suitable controlled release polymer may be used, such as acrylicacid and methacrylic acid copolymers and various esters thereof, e.g.methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polyacrylamide, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

Other suitable controlled release polymers include polymerizablequaternary ammonium compounds, e.g. quaternized aminoalkyl esters andaminoalkyl amides of acrylic acid and methacrylic acid, for exampleR-methacryloxyethyltrimethylammonium methosulfate,R-acryloxypropyltrimethylammonium chloride, andtrimethylaminomethylmethacrylamide methosulfate. The quaternary ammoniumatom can also be part of a heterocycle, as inmethacryloxyethylmethylmorpholinium chloride or the correspondingpiperidinium salt, or it can be joined to an acrylic acid group or amethacrylic acid group by way of a group containing hetero atoms, suchas a polyglycol ether group. Further suitable polymerizable quaternaryammonium compounds include quaternized vinyl-substituted nitrogenheterocycles such as methyl-vinyl pyridinium salts, vinyl esters ofquaternized amino carboxylic acids, styryltrialkyl ammonium salts, andthe like. Other polymerizable quaternary ammonium compoundsbenzyldimethylammoniumethylmethacrylate chloride,diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate,N-trimethylammoniumpropylmethacrylamide chloride, andN-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride. Delayedrelease may also achieved by using a controlled release polymer thattargets a particular pH, with the understanding that, with properfasting or feeding, the pH could correspond to a particular time afteradministration.

For some controlled release polymers, an acrylic or methacrylic polymercomprises one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers (such as those sold by Evonik under thetrademark EUDRAGIT® RS and RL) are fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. The ammonium groups are appended to the ester portionof the methacrylate (as 2-trimethylammonium-ethyl esters). The chargedammonium groups in these polymers make them insoluble and highlypermeable with pH-independent swelling. These properties make thesepolymers useful for customized, time-controlled release of the coateddrug. In order to obtain a desirable dissolution profile for a giventherapeutically active agent, such as reboxetine, two or more ammoniomethacrylate copolymers having differing physical properties can beincorporated. For example, it is known that by changing the molar ratioof the pre-polymerized materials containing quaternary ammonium groupsto pre-polymerized materials containing the uncharged, neutralmethacrylic or acrylic esters, the permeability properties of theresultant coating can be modified.

In other embodiments, the control releasing coat further includes apolymer whose permeability is pH dependent, such as anionic polymerssynthesized from methacrylic acid and methacrylic acid methyl ester.Such polymers are commercially available, e.g., from Evonik, under thetradename EUDRAGIT® L and EUDRAGIT® S. The ratio of free carboxyl groupsto the esters is known to be 1:1 in EUDRAGIT® L and 1:2 in EUDRAGIT® S.EUDRAGIT® L is insoluble in acids and pure water, but becomesincreasingly permeable above pH 5.0. This makes EUDRAGIT® L appropriatefor targeting release of the coated drug substance such as reboxetine inthe duodenum and the jejunum of the small intestine. Thus, a EUDRAGIT® Lcoated drug substance may achieve a delay in maximum plasmaconcentration, relative to an uncoated or immediate release drugsubstance (e.g. reboxetine in a first release component), of about 30min to about 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5hours, about 2.5-3 hours, or about 3.5-4 hours.

EUDRAGIT® S is similar to EUDRAGIT® L, except that it becomesincreasingly permeable above pH 7. This makes EUDRAGIT® S appropriatefor targeting release of the coated drug substance such as reboxetine inthe ileum of the small intestine and also the colon. Thus, a EUDRAGIT® Scoated drug substance may achieve a delay in maximum plasmaconcentration, relative to an uncoated or immediate release drugsubstance (e.g. reboxetine in a first release component), of about 1-2hours, about 2-3 hours, about 3-4 hours about 4-5 hours, about 5-6hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10hours.

A hydrophobic acrylic polymer coating can also include a polymer whichis based on dimethylaminoethyl methacrylate and neutral methacrylic acidesters (such as EUDRAGIT® E, commercially available from Evonik).EUDRAGIT® E is not soluble in saliva (making it useful for taste andodor masking) but is soluble in gastric fluid up to pH 5 which providesan immediate release of drug product in the stomach. Reboxetinesurrounded with a EUDRAGIT® E coating may release reboxetine, may beginreleasing reboxetine, or may have a first local maximum in the plasmaconcentration of reboxetine, at a time of about 0-30 minutes, 30-60minutes, 60-90 minutes, or 90-120 minutes after the dosage form isorally administered, or any time period in a range bounded by any ofthese values.

A hydrophobic acrylic polymer coating can include a neutral copolymerbased on a poly methacrylate, such as EUDRAGIT® NE (NE=neutral ester),commercially available from Evonik. EUDRAGIT® NE 30D lacquer films areinsoluble in water and digestive fluids, but permeable and swellable,providing another option for time-controlled release. EUDRAGIT® NE has apH-independent sustained release effect that can release a drugsubstance such as reboxetine over a period of time, or may delay releasefor a period of time, wherein the time of release or delay is about 1-24hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6hours.

In some embodiments, the control releasing coat comprises a polymercomprising ethyl acrylate and methyl methacrylate in a 2:1 ratio(KOLLICOAT® EMM 30 D, BASF). KOLLICOAT® EMM 30 D has a pH-independentsustained release effect that can release a drug substance such asreboxetine over a period of time, or may delay release for a period oftime, wherein the time of release or delay is about 1-24 hours, about1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the control releasing coat comprises a polyvinylacetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfatesuch as KOLLICOAT® SR30D (BASF). The dissolution profile can by alteredby changing the relative amounts of different acrylic resin lacquersincluded in the coating. Also, by changing the molar ratio ofpolymerizable permeability-enhancing agent (e.g., the quaternaryammonium compounds) to the neutral methacrylic esters, the permeabilityproperties (and thus the dissolution profile) of the resultant coatingcan be modified. KOLLICOAT® SR30D is another coating with apH-independent sustained release effect that can release a drugsubstance such as reboxetine over a period of time, or may delay releasefor a period of time, wherein the time of release or delay is about 1-24hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6hours, about 1-4 hours, or about 1-2 hours.

In some embodiments, the control releasing coat comprisesethylcellulose, which can be used as a dry polymer (such as ETHOCEL™,Dow Chemical Company) solubilized in organic solvent prior to use, or asan aqueous dispersion. One suitable commercially-available aqueousdispersion of ethylcellulose is Aquacoat® (Danisco). Aquacoat® ECD(ethylcellulose aqueous dispersion) Aquacoat® ARC (alcohol-resistantethylcellulose aqueous dispersion) Aquacoat® CPD (cellulose acetatephthalate aqueous dispersion) are all commercially available controlledrelease coatings. Another suitable aqueous dispersion of ethylcelluloseis commercially available as Surelease® (Colorcon, Inc.). This productcan be prepared by incorporating plasticizer into the dispersion duringthe manufacturing process. A hot melt of a polymer, plasticizer (e.g.dibutyl sebacate), and stabilizer (e.g. oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly ontosubstrates. These coatings have a pH-independent sustained releaseeffect that can release a drug substance such as reboxetine over aperiod of time, or may delay release for a period of time, wherein thetime of release or delay is about 1-24 hours, about 1-18 hours, about1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about1-2 hours.

Other examples of polymers that can be used in the control-releasingcoat include cellulose acetate phthalate, cellulose acetate trimaleate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethylcellulose, gelatin, starch, and cellulose based cross-linked polymers inwhich the degree of crosslinking is low so as to facilitate adsorptionof water and expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilicpolymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic andcationic hydrogels, zein, polyamides, polyvinyl alcohol having a lowacetate residual, a swellable mixture of agar and carboxymethylcellulose, copolymers of maleic anhydride and styrene, ethylene,propylene or isobutylene, pectin (molecular weight 30 k to 300 k),polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar, polyacrylamides, POLYOX® polyethylene oxides (molecular weight 100k to 5000 k, Dow), AQUA KEEP® acrylate polymers (composed of mainlyacrylic acid polymer, sodium salt), diesters of polyglucan, crosslinkedpolyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymerssuch as polysaccharides, methyl cellulose, sodium or calciumcarboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethylcellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxyethylcellulose, cellulose acetate, cellulose butyrate, cellulosepropionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acidesters, polyacrylamide, polyacrylic acid, natural gums, lecithins,pectin, alginates, ammonia alginate, sodium, calcium, potassiumalginates, propylene glycol alginate, agar, and gums such as arabic,karaya, locust bean, tragacanth, carrageenan, guar, xanthan,scleroglucan and mixtures and blends thereof.

In some embodiments, the dosage forms of reboxetine are coated withpolymers in order to facilitate mucoadhesion within the gastrointestinaltract. Non-limiting examples of polymers that can be used formucoadhesion include carboxymethylcellulose, polyacrylic acid, Carbopol™(Lubrizol), polycarbophil, gelatin and other natural or syntheticpolymers.

The polymeric coatings of the present disclosure may be any one of thedescribed coatings or may be a combination of two or more of thedescribed coatings to achieve the desired release profiles of therelease of reboxetine.

In addition to the modified release dosage forms described herein, othermodified release technologies known to those skilled in the art can beused in order to achieve the modified release formulations of thepresent disclosure, i.e., formulations which provide a mean T_(max) ofthe drug and/or other pharmacokinetic parameters described herein whenadministered e.g., orally or by other mode of administration to humanpatients. Such formulations can be manufactured as a modified releaseoral formulation in a suitable tablet or multiparticulate formulationknown to those skilled in the art. In either case, the modified releasedosage form can optionally include a controlled release carrier which isincorporated into a matrix along with the drug, or which is applied as acontrolled release coating.

Any dosage form comprising an effective amount of reboxetine may furthercomprise a binder, a lubricant, and other conventional inert excipients.

A binder (also sometimes called adhesive) can be added to a drug-fillermixture to increase the mechanical strength of the granules and tabletsduring formation. Binders can be added to the formulation in differentways: (1) as a dry powder, which is mixed with other ingredients beforewet agglomeration, (2) as a solution, which is used as agglomerationliquid during wet agglomeration, and is referred to as a solutionbinder, and (3) as a dry powder, which is mixed with the otheringredients before compaction. In this form the binder is referred to asa dry binder. Solution binders are a common way of incorporating abinder into granules. In certain embodiments, the binder used in thetablets is in the form of a solution binder. Non-limiting examples ofbinders useful for the core include hydrogenated vegetable oil, castoroil, paraffin, higher aliphatic alcohols, higher aliphatic acids, longchain fatty acids, fatty acid esters, wax-like materials such as fattyalcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats,hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobicand hydrophilic polymers having hydrocarbon backbones, and mixturesthereof. Specific examples of water-soluble polymer binders includemodified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives(e.g. hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose(HPC)), polyvinyl alcohol and mixtures thereof. Any suitable amount ofbinder may be present, such as about 0.5-5%, about 5-10%, about 10-15%,about 15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, orabout 3% by weight of the tablet dry weight. In some embodiments, thebinder is polyvinyl alcohol.

Lubricants can be added to pharmaceutical formulations to decrease anyfriction that occurs between the solid and the die wall during tabletmanufacturing. High friction during tableting can cause a series ofproblems, including inadequate tablet quality (capping or evenfragmentation of tablets during ejection, and vertical scratches ontablet edges) and may even stop production. Accordingly, lubricants maybe added to tablet formulations. Non-limiting examples of lubricantsuseful for the core include glyceryl behenate, stearic acid,hydrogenated vegetable oils (such as hydrogenated cottonseed oil(STEROTEX®, hydrogenated soybean oil (STEROTEX® HM) and hydrogenatedsoybean oil & castor wax (STEROTEX® K), stearyl alcohol, leucine,polyethylene glycol (MW 1450, suitably 4000, and higher), magnesiumstearate, glyceryl monostearate, stearic acid, polyethylene glycol,ethylene oxide polymers (for example, available under the registeredtrademark CARBOWAX® from Union Carbide, Inc., Danbury, Conn.), sodiumlauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearylfumarate, DL-leucine, colloidal silica, mixtures thereof and others asknown in the art. In some embodiments, the lubricant is glycerylbehenate (for example, COMPRITOL® 888). Any suitable amount of bindermay be present, such as about 0.5-5%, about 5-10%, about 10-15%, about15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, or about3% by weight of the tablet dry weight.

Dosage Forms (A) Multi-Layer Single Dosage Form Having 2 ReleaseComponents in a Layered Core Configuration

One specific aspect of the present disclosure comprises a controlledrelease dosage form having an inner layer, or a core, comprisingreboxetine and conventional excipients. In some embodiments, the core ofthe dosage form can be surrounded by a controlled release coat, whichdelays or sustains the release of the reboxetine. The dosage form maycomprise one or more additional functional or non-functional coatssurrounding the core or controlled release coat. In at least oneembodiment, the core's controlled release coat is surrounded by at leastone coating containing reboxetine. The outer reboxetine layer or coatingmay be further surrounded by an immediate release coating or anothercontrolled release coating. The controlled release single dosage formmay be a pill, tablet, capsule, caplet, or cachou.

The multi-layer single dosage form comprises, in total, an effectiveamount of reboxetine that is about 2-12 mg, about 2-4 mg, about 3-5 mg,about 4-6 mg, about 5-7 mg, about 6-8 mg, about 7-9 mg, about 8-10 mg,about 9-11 mg, about 10-12 mg, 12-16 mg, or about 8 mg.

The amount of the reboxetine present in the core of a multi-layer singledosage form can vary in an amount from about 0.01% to about 90% byweight of the total dry weight of the single dosage form. For example,in certain embodiments the amount of reboxetine is present in the coreof a multi-layer single dosage form in an amount from about 1-10%, about10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about60-70%, about 70-80%, about 80-90%, about 40-60%, about 0.01-5%, about5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, about30-35%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about55-60%, about 40%, about 45%, or about 50% of the total dry weight ofthe multi-layer single dosage form. For example, in certain embodiments,the core comprises about 0.5-1 mg, about 1-2 mg, about 2-3 mg, about 3-4mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7mg, or about 8 mg of reboxetine.

The core of the multi-layer single dosage form comprises an effectiveamount of reboxetine and may further comprise a binder, a lubricant, andother conventional inert excipients.

For some multi-layer dosage forms, the core may be surrounded by any ofthe controlled release polymers described above. In other embodiments,the core of the multi-layer single dosage form may be dispersed in anyof the controlled release polymers described above. For example, in oneembodiment, the core is surrounded by a delayed release coating. In someexamples, the delayed release coating comprises EUDRAGIT® S. The delayedrelease coating of the core may result in a delay of the release of thereboxetine of the core of about 1-2 hours, about 2-3 hours, about 3-4hours about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8hours, about 8-9 hours, or about 9-10 hours. In other embodiments, thecore is surrounded by a sustained release coating. In another example,the core is surrounded by or dispersed in a coating comprisingKOLLICOAT® EMM 30 D. The sustained release coating (or dispersion) ofthe core may result in a prolonged release of the reboxetine of the coreover about 1-2 hours, about 1-3 hours, about 1-4 hours, about 1-5 hours,about 1-6 hours, about 1-7 hours, about 1-8 hours, about 1-9 hours about1-10 hours, about 1-11 hours, about 1-12 hours, about 1-13 hours, about1-14 hours, about 1-15 hours, about 1-16 hours, or about 2 hours, about3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours,about 8 hours, about 9 hours, or about 10 hours.

Any of the controlled release reboxetine cores described herein may becoated with additional outer layers, at least one of which comprisesreboxetine. In some cases, the outer layer containing reboxetine may beoptionally surrounded by a controlled release coating or anotherfunctional or non-functional coating. In other embodiments, the outerlayer containing reboxetine may be optionally dispersed throughout acontrolled or sustained release polymer or another functional releasecoating. The outer layer containing reboxetine may contain an amount ofreboxetine less than, equal to, or greater than the amount of reboxetinecontained in the inner core structure. The outer layer of the controlledrelease multi-layer single dosage form may comprise an effective amountof reboxetine, a binder, a lubricant and can contain other conventionalinert excipients.

The amount of the reboxetine present in the outer layer of a multi-layersingle dosage form can vary in an amount from about 0.01% to about 90%by weight of the dry weight of the single dosage form. For example, incertain embodiments reboxetine in the outer layer is present in anamount from 40% to 60% by weight of the single dosage form's dry weight.For example, in certain embodiments, the outer layer of the multi-layersingle dosage form of the present disclosure comprises reboxetine in aproportion of about 1-10%, about 10-20%, about 20-30%, about 30-40%,about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 30%, about 0.01-5%, about 5-10%, about 10-15%, about 15-20%, about20-25%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about45-50%, about 50-55%, about 55-60%, about 60-65% about 65-70%, about45%, about 50%, or about 55% of the total dry weight of the multi-layersingle dosage form. For example, in certain embodiments, the outer layercomprises about 0.5-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg,about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg,about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg,or about 8 mg of reboxetine.

For some multi-layer single dosage forms, the outer reboxetine layer maybe surrounded by any of the controlled release polymers described above.In other embodiments, the outer reboxetine layer of the multi-layersingle dosage form may be dispersed in any of the controlled releasepolymers described above. For example, in one embodiment, the outerreboxetine layer is surrounded by an immediate release coating. In someexamples, the immediate release coating comprises EUDRAGIT® E. Theimmediate release coating of the outer reboxetine layer may result inthe complete release of the reboxetine of the outer reboxetine layer inabout 1-5 minutes, about 5-10 minutes, about 10-15 minutes, about 15-20minutes, about 20-25 minutes, about 25-30 minutes, about 30-60 minutes,about 60-90 minutes, or about 90-120 minutes. In other embodiments, theouter reboxetine layer is surrounded by or dispersed in a sustainedrelease coating. In another example, the outer reboxetine layer issurrounded by or dispersed in a polymer comprising polyvinylpyrrolidoneand/or cellulose derivatives. The polymer coating (or dispersion) of thecore may result in a release of the reboxetine of the core over about1-5 minutes, about 5-10 minutes, about 10-15 minutes, about 15-20minutes, about 20-25 minutes, about 25-30 minutes, about 30-60 minutes,about 60-90 minutes, or about 90-120 minutes.

In at least one embodiment, a multi-layer single dosage form contains atotal amount of reboxetine that is about 0.1-16 mg, such as about 0.1-1mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 5-6 mg, about 6-7mg, about 7-8 mg, about 8-9 mg, about 9-10 mg about 10-11 mg, about11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16mg, about 0.1-5 mg, about 5-10 mg, about 10-16 mg, about 2-6 mg, about6-10 mg, or about 7-9 mg. In some embodiments, the reboxetine is presentat from 0.1-85% by weight of the dry weight of the multi-layer singledosage form, such as about 0.1-5%, about 5-10%, about 10-15%, about15-20%, about 20-30%, about 30-40%, about 40-50%, about 50-70%, or about70-90%. In embodiments wherein reboxetine is present in both an outerlayer and an inner core layer, it is understood that the release of theouter layer of reboxetine precedes the release of the inner layer orcore of reboxetine. Thus the first pulse of reboxetine is from the outerlayer followed at a later time by the second pulse of reboxetine fromthe inner layer or core.

In other embodiments, a moisture barrier can optionally be added tosurround the outermost controlled release coat. If present, thismoisture barrier may affect in vitro drug release as well as precludingmoisture from coming into contact with the reboxetine.

In one embodiment, the outer layer containing reboxetine is an immediaterelease formulation of reboxetine.

In one embodiment, the inner core containing reboxetine is a coated witha controlled release layer wherein the reboxetine is released 2-6 hoursafter the initial release outer layer.

In another aspect, the single dosage form is administered within twohours after waking from an overnight sleep.

(B) Bi-Layer Single Dosage Form Having 2 Release Components in aLayer-On-Layer Configuration

In another specific feature of the present disclosure, two or morelayers containing reboxetine may be incorporated in a single dosageform, wherein the layers are physically bound to one another. In someembodiments, the layers are positioned on top of one another. In otherembodiments, the layers are positioned side-by-side. In some cases, thebi-layer single dosage form may be a pill, tablet, capsule, caplet, orcachou. Bi-layer tablets are a dosage form of particular interest.

In some examples, the first layer of a bi-layer single dosage form hasthe composition and properties described above for the outer reboxetinelayer, and its coating layer, of the multi-layer single dosage formdescribed above in part (A). In some cases, the second layer of abi-layer single dosage form has the composition and properties describedabove for the inner (or core) reboxetine layer, and its coating layer,of the multi-layer single dosage form described above in part (A). In atleast one embodiment, the first layer of the bi-layer single dosage formcorresponds to the first reboxetine release component, and the secondlayer of the bi-layer single dosage form corresponds to the secondreboxetine release component, both of which are described in detailabove.

In embodiments wherein reboxetine is present in both a first layer and asecond layer, it is understood that the release of reboxetine from thefirst layer precedes the release of the reboxetine from the secondlayer. Thus, the first pulse of reboxetine is from the first layer,followed at a later time by the second pulse of reboxetine from thesecond layer.

In one embodiment, the first layer of a bi-layer single dosage formcontaining reboxetine is surrounded by an immediate release coatinglayer.

In another embodiment, the second layer of a bi-layer single dosage formcontaining reboxetine is coated with, or dispersed in, a controlledrelease layer wherein the reboxetine is released 2-6 hours after therelease of the reboxetine from the first layer.

In some embodiments, the entire multi-layer dosage form is surrounded byan immediate release coating layer, with the understanding that thesecond layer of the bi-layer dosage form is coated with, or dispersedin, a controlled release layer wherein the reboxetine of the secondlayer is released 2-6 hours after the release of the reboxetine from thefirst layer.

In another example, the bi-layer single dosage form is administeredwithin two hours after waking from an overnight sleep.

(C) Multi-Particle Single Dosage Form Having 2 Release Components

In another specific aspect of the present disclosure, two or morevarieties of a controlled release core particle are incorporated into asingle formulation wherein the two or more particle varieties are notphysically attached to one another. In this aspect, the two or moreparticle types are contained within a single structure which may or maynot be surrounded by a control releasing coating. This structure may bein the form of a capsule, a caplet, a tablet, a cachou or the like.

In some examples, the first particle component of the multi-particlesingle dosage form has the composition and properties described abovefor the outer reboxetine layer, and its coating layer, of themulti-layer single dosage form described above in part (A). In somecases, the second particle component of the multi-particle single dosageform has the composition and properties described above for the inner(or core) reboxetine layer, and its coating layer, of the multi-layersingle dosage form described above in part (A). In at least oneembodiment, the first particle component of the multi-particle singledosage form corresponds to the first release component, and the secondparticle component of the multi-particle single dosage form correspondsto the second release component.

In embodiments wherein reboxetine is present in both a first particlecomponent and a second particle component, it is understood that therelease of reboxetine from the first particle component precedes therelease of the reboxetine from the second particle component. Thus thefirst pulse of reboxetine is from the first particle component, followedat a later time by the second pulse of reboxetine from the secondparticle component.

In one embodiment, the first particle component of a multi-particlesingle dosage form containing reboxetine is surrounded by an immediaterelease coating layer.

In some embodiments, the second particle component of a multi-particlesingle dosage form containing reboxetine is coated with a controlledrelease layer wherein the reboxetine is released 2-6 hours after therelease of the reboxetine from the first particle component.

In some examples, the multi-particle single dosage form is administeredwithin two hours after waking from an overnight sleep.

(D) First Dosage Form and Second Dosage Form Administered at SpecificTime Intervals

Another specific aspect of the present disclosure is the administrationof two or more controlled release dosage forms at specific timeintervals. The two or more controlled release dosage forms may beidentical in composition, comprising a core of reboxetine andconventional excipients. The core can be surrounded by a controlledrelease coat that may provide immediate release, delayed release,sustained release, or extended release of the reboxetine. This dosagemay be in the form of a capsule, a caplet, a tablet, a cachou or thelike.

In some examples, the reboxetine is delivered in a controlled releasedosage form, such as tablet, comprising: (i) a core that includesreboxetine (e.g. from 40% to 99% by weight of tablet dry weight), abinder such as polyvinyl alcohol (e.g. from 0.5% to 25% by weight oftablet dry weight), and a lubricant such as glyceryl behenate (e.g. from0.1% to 5% by weight of tablet dry weight); and (ii) a control releasingcoat that includes a water-insoluble water-permeable film-formingpolymer such as ethylcellulose (e.g. from 1% to 12% by weight of tabletdry weight), a water-soluble polymer such as polyvinylpyrrolidone, (e.g.from 1.5% to 10% by weight of tablet dry weight), optionally aplasticizer such as dibutyl sebacate, polyethylene glycol 4000 or amixture thereof (e.g. from 0.5% to 4% by weight of tablet dry weight),and optionally a wax such as carnauba wax (e.g. from 0.01% to 0.05% byweight of tablet dry weight).

In at least one embodiment of the disclosure, the dosage form is a 5 mgtablet comprising: (i) a core that includes reboxetine (e.g. 80% byweight of tablet dry weight), a binder such as polyvinyl alcohol (e.g.3% by weight of tablet dry weight), and a lubricant such as glycerylbehenate (e.g. 3% by weight of tablet dry weight); and (ii) a controlreleasing coat that includes a water-insoluble water-permeablefilm-forming polymer such as ethylcellulose (e.g. 6% by weight of tabletdry weight), a water-soluble polymer such as polyvinylpyrrolidone (e.g.5% by weight of tablet dry weight), optionally a plasticizer such asdibutyl sebacate, polyethylene glycol 4000 or a mixture thereof (e.g. 3%by weight of tablet dry weight), and optionally a wax such as carnaubawax (e.g. 0.03% by weight of tablet dry weight).

In some embodiments, the core formulation is an uncoated immediaterelease formulation resulting in 100% dissolution of the reboxetinewithin 1 hour, within 45 minutes, within 30 minutes, within 15 minutes,within 10 minutes, within 5 minutes, or within 1 minute. In at least oneembodiment, the core is a normal release matrix formulation. In certainembodiments, the core comprises an effective pharmaceutical amount ofreboxetine, a binder (e.g. polyvinyl alcohol), and a lubricant (e.g.glyceryl behenate). Additional inert excipients can also be added to thecore formulation. The additional inert excipients can be added tofacilitate the preparation and/or improve patient acceptability of thefinal extended-release dosage form as described herein. The additionalinert excipients are well known to the skilled artisan and can be foundin the relevant literature, for example in the Handbook ofPharmaceutical Excipients. Non-limiting examples of such excipientsinclude spray dried lactose, sorbitol, mannitol, and any cellulosederivative.

In some embodiments, the controlled release dosage form has thecomposition and properties described above for the outer reboxetinelayer of the multi-layer single dosage form described above in part (A).In some cases, the controlled release dosage form has the compositionand properties described above for the inner (or core) reboxetine layerof the multi-layer single dosage form described above in part (A).Typically, the first controlled release dosage form corresponds to thefirst reboxetine release component, and the second controlled releasedosage form corresponds to the second reboxetine release component.

It is generally understood that the release of reboxetine from the firstcontrolled release dosage form precedes the release of the reboxetinefrom the second controlled release dosage form. Therefore, the firstmaximum plasma concentration of reboxetine is from the first controlledrelease dosage form, followed at a later time by the second maximumplasma concentration of reboxetine from the second controlled releasedosage form.

In some embodiments, the administration of the first controlled releasedosage form is administered about 2 hours to about 8 hours before theadministration of the second controlled release dosage form. Inadditional embodiments, the second controlled release dosage form isadministered about 2-3 hours, about 3-4 hours, about 4-5 hours, about5-6 hours, about 6-7 hours, about 7-8 hours, about 4 hours, about 5hours, or about 6 hours after administration of the first controlledrelease dosage form.

In one embodiment, the first controlled release single dosage formcontaining reboxetine is surrounded by an immediate release coatinglayer.

In some embodiments, the first controlled release single dosage formcontaining reboxetine is coated with a controlled release layer whereinthe reboxetine is released 1-6 hours after administration.

In some cases, the first controlled release single dosage form isadministered within two hours after waking from an overnight sleep.

(E) First Dosage Form and Second Dosage Form Administered at the SameTime

In another embodiment of the present disclosure, two or morenon-identical controlled release dosage forms are administered at aboutthe same time. The two or more controlled release dosage forms eachcomprise a core of reboxetine and conventional excipients, as describedabove in part (D). In one embodiment, the two or more dosage formscomprise differing controlled release coatings, analogous to the coreand the outer layer as described above in part (A). In one example, afirst dosage form of reboxetine is uncoated, or is surrounded by animmediate release coating, and a second dosage form is surrounded by adelayed, sustained, or extended release coating. Both dosage forms maybe in the form of a capsule, a caplet, a tablet, a cachou or the like.

In some embodiments, the first controlled release dosage form has thecomposition and properties described above for the outer reboxetinelayer of the multi-layer single dosage form described above in part (A).In some cases, the controlled release dosage form has the compositionand properties described above for the inner (or core) reboxetine layerof the multi-layer single dosage form described above in part (A).Typically, the first controlled release dosage form has the compositionand properties of the first reboxetine release component, and the secondcontrolled release dosage form has the composition and properties of thesecond reboxetine release component. In one example, the firstcontrolled release dosage form containing reboxetine is surrounded by animmediate release coating layer.

In some cases, the second controlled release dosage form containingreboxetine is coated with a controlled release layer wherein thereboxetine is released 2-6 hours after the release of the reboxetinefrom the first controlled release dosage form.

In some embodiments, a first local maximum provided by the firstcontrolled release dosage form occurs about 2 hours to about 6 hoursprior to the second local maximum provided by the second controlledrelease dosage form.

In some examples, the first controlled release single dosage form isadministered within two hours after waking from an overnight sleep.

(F) Other Delivery Methods

Other controlled release drug formulations are optionally contemplatedin the present disclosure. In some embodiments, reboxetine isadministered in both a long-term controlled release manner (by the useof a patch or similar dermal adhesive drug delivery device) and also adaily treatment manner. In some examples, reboxetine is delivered to apatient in the form of an implanted device. In this particularembodiment, reboxetine may be incorporated into a slowly degradingpolymer to release the drug slowly over time. The time period forcomplete degradation and release of drugs from such an implant may be1-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, 12-16 weeks, 16-18 weeks,2-6 months, 6-12 months or any time period in a range bounded by any ofthese values. Reboxetine may be incorporated into another polymericimplant device wherein the reboxetine is released in a pulse-like mannerfrom individual wells in the polymeric device. In this embodiment, thewells containing drug are coated with controlled release membranes thatrelease drug in distinctly timed pulses. These membranes would beconstructed of the controlled release coating described herein. Thedevice containing the wells may itself degrade over time. The timeperiod for complete release of drugs from such an implant may be 1-4weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, 12-16 weeks, 16-18 weeks, 2-6months, 6-12 months or any time period in a range bounded by any ofthese values.

It is envisioned that the amount of drug delivered from the devicesabove would provide a low steady state concentration of reboxetine whichwould fall below the maximum plasma concentration associated with adosage forms described herein. While the reboxetine is administeredchronically by a long-term controlled release device, it is envisionedthat reboxetine may also be administered in a daily dose of one of theabove formulations described in part (D).

The reboxetine may be provided to the blood of a human being fortreating psychiatric or neurological disorders, such as depression,including major depressive disorder or treatment-resistant depression,and narcolepsy, including narcolepsy with cataplexy and/or excessivedaytime sleepiness.

The following embodiments are specifically contemplated.

EMBODIMENTS

Embodiment 1. A method of providing reboxetine to the blood of a humanbeing comprising: administering reboxetine to a human being in need oftreatment with reboxetine in a manner that results in:

1) a first local maximum in reboxetine plasma concentration, and

2) a second local maximum in reboxetine plasma concentration;

wherein the first local maximum occurs about 2 hours to about 6 hoursprior to the second local maximum.

Embodiment 2. The method of embodiment 1, wherein the reboxetine isadministered in a single dosage form that provides both: 1) the firstlocal maximum in reboxetine plasma concentration and 2) the second localmaximum in reboxetine plasma concentration, wherein the single dosageform is administered within two hours after waking from an overnightsleep.Embodiment 3. The method of embodiment 2, wherein the single dosage formis a single pill, tablet, capsule, caplet or cachou.Embodiment 4. The method of embodiment 2 or 3, wherein the single dosageform comprises an inner core containing reboxetine and an outer coatinglayer containing reboxetine.Embodiment 5. The method of embodiment 4, wherein an inner controlledrelease coating is disposed between the inner core containing reboxetineand the outer coating layer containing reboxetine.Embodiment 6. The method of embodiment 5, wherein the inner controlledrelease coating provides delayed release of the inner core containingreboxetine.Embodiment 7. The method of embodiment 5 or 6, wherein the outer coatinglayer comprising reboxetine is further surrounded by an outer controlledrelease layer.Embodiment 8. The method of embodiment 7, wherein the outer controlledrelease layer provides delayed release of the outer coating layercontaining reboxetine.Embodiment 9. The method of embodiment 7, wherein the outer controlledrelease layer provides immediate release of the outer coating layercontaining reboxetine.Embodiment 10. The method of embodiment 2 or 3, wherein the singledosage form comprises reboxetine in a first controlled release layer anda second controlled release layer, wherein the controlled release layersare physically bound to one another in a bi-layer structure.Embodiment 11. The method of embodiment 10, wherein the first controlledrelease layer is coated with a first controlled release coating, and thesecond controlled release layer is coated with a second controlledrelease coating.Embodiment 12. The method of embodiment 11, wherein the first controlledrelease coating provides immediate release of the first controlledrelease layer.Embodiment 13. The method of embodiment 11 or 12, wherein the secondcontrolled release coating provides delayed release of the secondcontrolled release layer.Embodiment 14. The method of embodiment 2 or 3, wherein the singledosage form comprises reboxetine in a first controlled release componentand a second controlled release component, wherein the controlledrelease components are not physically bound to one another.Embodiment 15. The method of embodiment 14, wherein the first controlledrelease component provides immediate release of reboxetine.Embodiment 16. The method of embodiment 14 or 15, wherein the secondcontrolled release component provides delayed release of reboxetine.Embodiment 17. The method of embodiment 1, wherein the reboxetine isadministered in a first dosage form that provides: 1) the first localmaximum in reboxetine plasma concentration; and a second dosage formthat provides: 2) the second local maximum in reboxetine plasmaconcentration; wherein the first dosage form is administered within twohours after waking from an overnight sleep.Embodiment 18. The method of embodiment 17, wherein the first dosageform and the second dosage forms are identical, and the second dosageform is administered to the human being about 2 hours to about 6 hoursafter the first dosage form is administered.Embodiment 19. The method of embodiment 18, wherein the second dosageform containing reboxetine is administered to the human being about 6hours after the first dosage form is administered.Embodiment 20. The method of embodiment 17, wherein the first dosageform and the second dosage forms are not identical, wherein the firstdosage form and the second dosage form is administered at about the sametime to the human being, and the second dosage form releases reboxetineabout 2 hours to about 6 hours after the first dosage form releasesreboxetine.Embodiment 21. The method of embodiment 20, wherein the first dosageform provides immediate release of reboxetine.Embodiment 22. The method of embodiment 20 or 21, wherein the seconddosage form provides delayed release of reboxetine.Embodiment 23. The method of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, or 16, wherein the single dosage form of reboxetine isadministered once per day.Embodiment 24. The method of embodiment 17, 18, 19, 20, 21 or 22,wherein the first dosage form and the second dosage form are eachadministered once per day.

While the present invention has been shown and described in connectionwith the embodiments, it will be apparent to those skilled in the artthat modifications and variations can be made without departing from thespirit and scope of the invention as defined by the appendedembodiments.

The terms “a”, “an”, “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingembodiments) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All method described herein can be performed in any suitableorder unless otherwise indicated herein or contradicted by context. Theuse of any and all examples or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the inventionand does not pose a limitation on the scope of any embodiment. Nolanguage in the specification should be construed as indicating anynon-embodied element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand embodied individually or in any combination with other members ofthe group or other elements found herein. It is anticipated that one ormore members of a group may be included in, or deleted from, a group forreasons of convenience.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments, will become apparent to those orordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than specifically described herein. Accordingly, theembodiments include all modifications and equivalents, or the subjectmatter recited in the embodiments as permitted by applicable law.Moreover, any combination of the above described elements in allpossible variations thereof is contemplated unless otherwise indicatedherein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the embodiments. Thus, by way ofexample, but not limitation, alternative embodiments may be utilized inaccordance with the teachings herein. Accordingly, the embodiments arenot limited to embodiments precisely as shown or described.

1. A pharmaceutical product comprising a single dosage form and a label,wherein the single dosage form comprises a first release component and asecond release component, wherein the first release component contains 1mg to 10 mg of reboxetine, and the second release component contains 0.1mg to 10 mg of reboxetine and is coated with a polymer that delaysrelease of reboxetine in the second release component; wherein thesingle dosage form has a property that, when administered to a fastedhuman subject: 1) the reboxetine in the first release component providesa first local maximum in reboxetine plasma concentration, and 2) thereboxetine in the second release component provides a second localmaximum in reboxetine plasma concentration, wherein the first localmaximum in reboxetine plasma concentration occurs about 2 hours to about6 hours prior to the second local maximum in reboxetine plasmaconcentration; and wherein the label states that the single dosage formis to be administered once a day.
 2. The pharmaceutical product of claim1, wherein the polymer that delays release of reboxetine in the secondrelease component comprises an acrylic acid or an acrylate polymer. 3.The pharmaceutical product of claim 1, wherein the polymer that delaysrelease of reboxetine in the second release component comprises aquaternary ammonium compound.
 4. The pharmaceutical product of claim 1,wherein the polymer that delays release of reboxetine in the secondrelease component comprises a cellulose derivative.
 5. Thepharmaceutical product of claim 1, wherein the first release componentis free of any polymer that controls or delays release of reboxetine. 6.The pharmaceutical product of claim 1, wherein the second releasecomponent comprises an inner core containing the reboxetine and thefirst release component comprises an outer coating layer containing thereboxetine.
 7. The pharmaceutical product of claim 6, wherein thepolymer that delays release of reboxetine in the second releasecomponent is disposed between the inner core containing the reboxetineand the first release component.
 8. The pharmaceutical product of claim1, wherein the first release component comprises a first controlledrelease layer and the second release component comprises a secondcontrolled release layer, and the first controlled release layer and thesecond controlled release layer together form a bi-layer structure. 9.The pharmaceutical product of claim 8, wherein the first controlledrelease layer provides immediate release of reboxetine.
 10. Thepharmaceutical product of claim 1, wherein the first release componentcomprises a first release layer and the second release componentcomprises a second release layer, wherein the first release layer is notphysically bound to the second release layer.
 11. The pharmaceuticalproduct of claim 10, wherein the first release layer provides immediaterelease of reboxetine.
 12. The pharmaceutical product of claim 1,wherein the reboxetine is in the free base form.
 13. The pharmaceuticalproduct of claim 1, wherein the reboxetine is in a salt form.
 14. Thepharmaceutical product of claim 1, wherein the reboxetine is in the formof mesylate salt.
 15. The pharmaceutical product of claim 1, wherein thesingle dosage form is in the form of a pill, a tablet, a capsule, acaplet, or a cachou.
 16. The pharmaceutical product of claim 1, whereinthe single dosage form further comprises a binder.
 17. Thepharmaceutical product of claim 1, wherein the single dosage formfurther comprises a lubricant.
 18. The pharmaceutical product of claim1, wherein the single dosage form further comprises an inert excipient.19. The pharmaceutical product of claim 1, wherein the first releasecomponent contains 3 mg to 7 mg of reboxetine.
 20. The pharmaceuticalproduct of claim 1, wherein the second release component contains 0.1 mgto 7 mg of reboxetine.